Unopposed protease activity resulting from anti-elastase resistant supramolecular complexes of neutrophil elastase and shed syndecan-1 in the airway fluids is thought to be the cause of persistent inflammation resulting in airway damage and deteriorating lung function in COPD and bronchiectasis (1, 2). We aim to develop strategies to decrease syndecan-1 shedding for the treatment of COPD and bronchiectasis. The levels of heparanase, syndecan-1 and MMP-7 activity were measured in sputum samples of local patients. Values are means ± S.E.M., compared by Student’s T-test. The sputum from such patients contained elevated levels of heparanase (n=3, normalized pixel densities from Western blot, p<0.05) and shed syndecan-1 (200 ± 11 ng/ml in bronchiectasis patients n=13 and 128 ± 7 ng/ml in COPD patients n=20 vs 21 ± 4 ng/ml in induced sputum from healthy individuals n=5, p <0.05 respectively) but not elevated levels of matrix metalloproteinase (MMP) activity (3.22 ± 0.14 in COPD n=5 and 17.90 ± 5.06 in bronchiectasis n=5 vs 2.99 ± 1.36 μM/μg/min in induced sputum from healthy individuals n=3, p=0.8 and 0.04 respectively), we propose that the action of the GAG digesting enzyme heparanase on syndecan-1 modifies it such that it becomes more susceptible to shedding by MMP cleavage. We show in vitro that heparanase induced syndecan-1 shedding in air-liquid interface cultured human epithelial cells (shed syndecan concentration in medium 11.2 ± 0.7ng/ml vs 131.5 ± 1.8 ng/ml after heparanase treatment, p<0.05), and that heparanase-treated recombinant syndecan-1 was more readily cleaved by MMP-7 than control treatment of the recombinant syndecan-1(0.21 vs 1.22 ng/ml/h, determined by ELISA). Surface plasmon resonance analysis demonstrated an increase in affinity of syndecan-1 for MMP-7 upon heparanase treatment (affinity constant increase from 6.83 × 105 to 2.31 × 1010 M-1, n=5). Co-immunoprecipitation study targeting syndecan-1 found associated MMP-7 higher in the sputum samples of bronchiectasis and COPD patients than in induced sputum of healthy individuals; normalized pixel density ratios of MMP-7: syndecan-1 of bronchiectasis and COPD patients (7.0 and 5.7 vs 1.8 in induced sputum) reinforced the suggestion of increased affinity of MMP-7 for syndecan-1 that had been exposed to heparanase activity. The results support that heparanase activity in the inflammatory airway environment enhances shedding of syndecan-1 and thus a target for the treatment of bronchiectasis and COPD.